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LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis.
- Source :
-
Blood [Blood] 2019 Oct 03; Vol. 134 (14), pp. 1159-1175. Date of Electronic Publication: 2019 Jul 31. - Publication Year :
- 2019
-
Abstract
- Hematopoietic transcription factor LIM domain only 2 (LMO2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrate that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LIM domain binding 1 and activate the TAL1 complex. NAMPT/SIRT2-mediated activation of LMO2 by deacetylation appears to be important for hematopoietic differentiation of induced pluripotent stem cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX and NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.<br /> (© 2019 by The American Society of Hematology.)
- Subjects :
- Acetylation
Animals
Cells, Cultured
HEK293 Cells
Humans
Leukopoiesis
Mice
Models, Molecular
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
Zebrafish
Adaptor Proteins, Signal Transducing metabolism
Hematopoiesis
LIM Domain Proteins metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism
Proto-Oncogene Proteins metabolism
Transcription Factors metabolism
Zebrafish Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 134
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 31366618
- Full Text :
- https://doi.org/10.1182/blood.2019000095